Anti-plaque compositions comprising a combination of morpholinoamino alcohol and antibiotic

ABSTRACT

Compositions having improved anti-plaque and anti-gingivitis activity comprises a synergistic combination of a) a morpholinoamino alcohol, such as 3-(4-propylheptyl)-4-(2-hydroxyethyl)morpholine and b) and antibiotic, such as the aminoglycosides, amphenicols, ansamycins, carbapenems, cephalosporins, cephamycins, monobactams, oxacephems, penicillins, lincosamides, macrolides, polypeptides and tetracyclines.

BACKGROUND OF THE INVENTION AND INFORMATION DISCLOSURE

Bacterial aggregation on the teeth known as plaque has been identifiedas a cause of dental caries, gingivitis, periodontitis and other gumdiseases. Mechanical methods have been used for some time for theprevention of dental plaque but have not generally achieved sufficientresults. Studies have shown that mechanical methods such as the use ofdental floss and interspace brushes do not eliminate interproximalplaque. During the past decade or more chemical plaque control as asubstitute or supplement to mechanical methods has been tried.

Octapinol has been tested for its ability to reduce plaque formation andthe development of gingivitis by Willard, Edwardsson, Attstom andMatsson, "The effect of Octapinol on dento-gingival plaque anddevelopment of gingivitis", Journal of Periodontal Research, Volume 18,pages 429-437, (1983). Here it is reported that octapinol may preventthe development of plaque. Some adverse side effects of octapinol areits toxicity, lasting bitter taste and its brownish staining of theteeth.

U.S. Pat. No. 4,636,382 describes morpholino compounds which are usefulfor the inhibition or removal of dental plaque. The '382 patent alsodiscloses that a wide variety of chemical and biological agents havebeen suggested for the inhibition of plaque, such as penicillin,chlorohexidine, 8-hydroxyquinoline and ethylenediamine tetraacetate.However, many of these chemical and biological agents are described asexhibiting insignificant effects and often causing serious side effects.The morpholino compounds of the '382 patent are described as having alow antibacterial effect and lacking undesirable side effects such asdiscoloration of the teeth.

U.S. Pat. No. 4,610,871 describes the use of monoalkyl or dialkyl ethersof dianhydrohexitols to inhibit the formation of plaque and calculus onteeth. U.S. Pat. No. 4,178,363 describes the use of n-undecylenic acidor a calcium or zinc salt thereof for reducing dental plaque andinfections of the teeth and gums. U.S. Pat. No. 4,119,711 describesspiro 1-(hydroxyalkyl)-piperidino derivatives which have efficacy inreducing the formation of plaque. U.S. Pat. No. 3,976,765 describesbis-biguanido hexanes in combination with nonionic surfactants andcertain foam stabilizers for use in a variety of oral preparations.

Additionally, U.S. Pat. No. 3,887,712 discloses that alexidinedihydrofluoride is useful in the treatment of dental plaque, calculus,gingivitis and related periodontal diseases. U.S. Pat. No. 4,160,821discloses that a glycerins solution of zinc chloride or other acceptablezinc salts provides effective therapy for gingivitis when applied to thegingivae and teeth.

Efforts continue toward finding improved means for reducing and/oreliminating plaque without many of the side effects associated with theprior art, such as discoloration of teeth or tongue, desquamation andsoreness of oral mucosa, objectionable taste, toxicity and imbalance ofthe oral flora. It is an object of the present invention to providenovel compositions which are useful in the treatment of plaque andgingivitis without many of the adverse side effects associated withprior art compositions. It is another object of this invention toprovide anti-plaque compositions which would cause little or noecological imbalance of the oral flora. It is a further object of thisinvention to provide compositions comprising a combination of amorpholinoamino alcohol and an antibiotic wherein these compositionspossess synergistically improved anti-plaque and anti-gingivitisactivity.

SUMMARY OF THE INVENTION

The present invention relates to novel compositions comprising asynergistic combination of a morpholinoamino alcohol orpharmaceutically-acceptable salt thereof and an antibiotic. Themorpholinoamino alcohol has the chemical formula ##STR1## wherein R₁ isa straight or branched alkyl group containing 8 to 16 carbon atoms atthe 2- or 3- position of the morpholino ring, and R₂ is a straight orbranched alkyl group containing 2 to 10 carbon atoms terminating with ahydroxy group. The antibiotic includes the aminoglycosides; amphenicols;ansamycins; B-lactams such as carbapenems, cephalosporins, cephamycins,monobactams, oxacephems, and pencillins; lincosamides; macrolides;polypeptides; and tetracyclines.

The preferred morpholinoamino alcohol is3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine and the preferredantibiotics are the penicillins, tetracyclines and polymyxins. Thecompositions preferably comprise about 0.1-5% by weight of saidmorpholinoamino alcohol and about 10⁻³ molar to about 10⁻¹⁰ molar of theantibiotic.

The compositions of this invention are useful in a wide variety offormulations, such as, for example, toothpaste, mouth wash, chewing gunand other dentifrices to reduce plaque or gingivitis. These compositionshave synergistically improved anti-plaque and anti-gingivitis activitywith less side effects.

DETAILED DISCUSSION

This invention involves novel compositions which have improvedanti-plaque or anti-gingivitis activity. The novel compositions of thepresent invention comprise in combination a pharmaceutically effectiveamount of a) one or more morpholinoamino alcohol(s) orpharmaceutically-acceptable salt thereof and b) one or moreantibiotic(s).

The morpholinoamino alcohols useful according to this invention have thechemical formula ##STR2## wherein R₁ is a straight or branched alkylgroup containing 8 to 16 carbon atoms at the 2- or 3-position of themorpholino ring, and R₂ is a straight or branched alkyl group containing2 to 10 carbon atoms terminating with hydroxy group. Preferably, the sumof the carbon atoms in said groups R₁ and R₂ ranges from 10 to 20, morepreferably from 12 to 16. The morpholinoamino alcohols of this inventionare described in U.S. Pat. No. 4,636,382; the disclosure of which isherein incorporated by reference.

The morpholinoamino alcohols can be prepared by several processes asdescribed in U.S. Pat. No. 4,636,382, such as:

(a) by alkylating a morpholino derivative having the formula ##STR3##wherein R₁ is as defined above; with an alkylating agent of the formula

    R.sub.2 X

wherein R₂ is as defined above and X is halogen or an organic sulfonicester, or wherein X together with a hydroxyl group present in R₂ is areactive oxide;

(b) by ring closure of a compound having the general formula ##STR4##wherein R₁ is as defined above, X is halogen or an organic sulfonicester and A represents CH₂ groups, one CH₂ group being substituted withthe group R₁ ; with an amino alkanol of the general formula

    NH.sub.2 R.sub.2

wherein R₂ is as defined above:

(c) by reducing a mono- or di-oxo substituted morpholine having thegeneral formula ##STR5## wherein R₂ is as defined above, n is 0 or 1,and R₁ is as defined above and is at the 2-position when n is 1 and atthe 2- or 3-position when n is O, or

(d) by starting from a morpholino compound having the general formula##STR6## wherein R₁ is as defined above and R₃ is a straight or branchedalkyl group containing a group transformable to OH or CH₂ OH.

The most preferred morpholinoamino alcohol for use in this invention is3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine represented by thechemical formula ##STR7## Also most preferred is the hydrochloride saltof 3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine. This compound is awhite, odorless, crystalline powder which is very soluble in water,alcohols and chloroform and has a melting point of about 70° C.

The morpholinoamino alcohols of this invention can be used in their freebase form or as pharmaceutically - acceptacle salts thereof. Someexamples of pharmaceutically - acceptable salts are the salts of acidssuch as acetic acid, phosphoric acid, boric acid, hydrochloric acid,maleic acid, benzoic acid, citric acid, malic acid, oxalic acid,tartaric acid, succinic acid, glutaric acid, gentisic acid, valericacid, gallic acid, beta- resorcylic acid, acetyl salicylic acid,salicylic acid, perchloric acid, barbituric acid, sulfanilic acid,phytic acid, p-nitro benzoic acid, stearic acid, palmitic acid, oleicacid, myristic acid, lauric acid and the like. The most preferred saltsare those of hydrochloric acid.

As the morpholinamino alcohols of this invention by themselves have onlyweak anti-microbial activity, it is critical to the practice of thisinvention that said morpholinoamino alcohols be present in combinationwith one or more antibiotics. It is the synergistic combination of saidmorpholinoamino alcohol and an antibiotics which provides thecompositions of this invention with their improved anti-plaque andanti-gingivitis properties. Without being bound by any theory ormechanism of action, it is believed that these morpholinoamino alcoholsinhibit key bacterial membrane functions such as carbohydrate uptake,cellular permeability, cell metabolism and cell division. Bacterialcells which are weakened by these morpholinoamino alcohols are moreeffectively eradicated by antibiotic compounds. Thus, compositions ofthis invention comprising a combination of said morpholinoamino alcoholsand antibiotics are extremely effective in inhibiting plaque formationand reducing preformed plaque and for treating gingivitis. Thesecompositions have also demonstrated effectiveness in inhibiting acidproduction by bacteria, such as Streptococcus mutans, and thereforethese composition would have anti-caries activity.

Moreover, studies show a very low order of acute and subacute toxicity,no mutagenic activity, no adverse effect on reproduction and no stainingof teeth by the morpholinoamino alcohols of the present invention.

The antibiotics which are useful in combination with the morpholinoaminoalcohols of this invention include the aminoglycosides, amphenicols,ansamycins, B-lactams (such as the aztreonam carbapenems,cephalosporins, cephamycins, monobactams, oxacephems and penicillins),lincosamides, macrolides, polypepetides and tetracyclines. Theaminoglycosides include amikacin, apramycin, arbekacin, bambermycins,butirosin, dibekacin, dihydrostreptomycin, fortimicin, gentamicin,isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate,netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin,streptomycin, streptonicozid, tobramycin and the like. The amphenicolsinclude azidamfenicol, chloramphenicol, chloramphenicol palmitate,chloramphenicol pantothenate, florfenicol, thiamphenicol and the like.The ansamycins include rifamide, rifampin, rifamycin, rifaximin and thelike. The B-lactams include imipenem, cefaclor, cefadroxil, cefamandole,cefatrizine, cefazedone, cefazolin, cefixime, cefmenoxime, cefodizime,cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefpimizole,cefpiramide, cefpodoxime proxetil, cefroxadine, cefsulodin, ceftazidime,cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin,cephaloridine, cephalosporin c, cephalothin, cephamycin, cephapirinsodium, cephradine, pivcefalexin, cefbuperazone, cefmetazole, cefminox,cefotetan, cefoxitin, aztreonam, carumonam, tigemonam, flomoxef,moxolactam, oxacephems and the like. The B-lactams also include thepenicillins such as amidinocillin, amoxicillin, ampicillin, apalcillin,aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinicacid, benzylpenicillin sodium, carbenicillin, carfecillin sodium,carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin,diphenicillin sodium, epicillin, fenbenicillin, floxacillin, hetacillin,lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillinsodium, oxacillin, penamecillin, penethamate hydriodide,penimempicycline, phenethicillin potassium, piperacillin, pivampicillin,propicillin, quinacillin, sulbenicillin, talampicillin, temocillin,ticarcillin, and other penicillins such as penicillin G, penicillin N,penicillin O, penicillin V and the like.

The macrolides include azithormycin, carbomycin, clarithromycin,erythromycins, josamycin, leucomycins, midecamycins, miokamycin,oleandomycin, primycin, rokitamycin, rosaramicin, roxithromycin,spiramycin, troleandomycin and the like.

The polypeptides include amphomycin, bacitracin, capreomycin, colistin,enduracidin, enviomycin, fusafungine, gramicidins, mikamycin, polymyxin,polymyxin b-methanesulfonic acid, pristinamycin, ristocetin,teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, tyrothricin,vancomycin, viomycin, viomycin pantothenate, virginiamycin and the like.

The tetracyclines include apicycline, chlortetracycline, clomocyline,demeclocycline, doxycycline, guamecycline, lymecycline, meclocycline,methacycline, minocycline, oxytetracycline, penimepicycline,pipacycline, rolitetracycline, sancycline, senociclin, tetracycline andthe like. Other antibiotics useful according to this invention arenisin, nystatin, tylosin, pimaricin, cycloserine, mupirocin, tuberin,clindamycin, metronidazole, fluorquinolones, nitrofurantoin, rifampin,sulfonamides, trimethoprim, trimethoprim-sulfamethoxazole, cycloserine,ethambutol, ethionamide, isoniazid, pyrazinamide and rifampin.

The preferred antibiotics for use in this invention are the B-lactams,monobactams, tetracyclines and polymyxins.

In the compositions of this invention, the morpholinoamino alcohols arepresent preferably in an amount ranging from about 0.1% to about 5.0% bytotal weight of said compositions; more preferably from about 0.01% toabout 1.0%; and most preferably from about 0.05% to about 0.2%. Theamount of said antibiotics in the compositions of this inventionpreferably ranges from about 10⁻³ molar to about 10⁻¹⁰ molar by totalweight of said compositions; more preferably from about 10⁻⁴ molar toabout 10⁻⁹ molar; and most preferably from about 10⁻⁴ molar to about10⁻⁶.

The essence of the present invention is the synergistic effect ofinhibiting and reducing the growth of plaque bacteria, which is achievedwhen the morpholinoamino alcohols and the antibiotics are utilized incombination in effective concentrations in the oral cavity. Smallerquantities of each of these components are required to obtain effectiveinhibition of plaque and other bacteria than if each component wasutilized alone. Since lower quantities of each component can be used inthe compositions of this invention, the side effects associated witheach of the components would be correspondingly reduced or eliminated.

In one form of this invention, the composition may be a liquid such as amouthwash or rinse. In such a composition the vehicle is typically awater-alcohol mixture. Generally the ratio of water to alcohol is in therange of from about 1:1 to about 20:1, preferably about 3:1 to about20:1 and most preferably about 3:1 to about 10:1 by weight. The mostpreferred mouthwash or mouth rinse compositions comprise from 0 to about30% by weight alcohol such as ethanol. The total amount of water-alcoholcomposition in a mouthwash composition is typically in the range fromabout 70% to about 99.9% by weight of the composition. The pH value ofsuch mouthwash compositions is generally from about 4.0 to about 7.0 andpreferably from about 5 to about 6.5. A pH below 4 would be irritatingto the oral cavity. A pH greater than 7 would result in an unpleasantmouth feel.

Oral liquid compositions may also contain surface active agents inamounts up to about 5% and fluorine-providing compounds in amounts up toabout 2% by weight of the composition.

Surface active agents are organic materials which afford completedispersion of the composition throughout the oral cavity. The organicsurface active material may be non-ionic, amphoteric, or cationic.

Non-ionic surface active agents include condensates of sorbitanmono-oleate with from 20 to 60 moles of ethylene oxide (e.g., "Tweens" atrademark of ICI United States, Inc.), condensates of ethylene oxidewith propylene oxide and condensates of propylene glycol ("Pluronics" atrademark of BASF-Wyandotte Corp.).

Other suitable non-ionic surfactants are the condensation products of analpha-olefin oxide containing 10 to 20 carbon atoms, a polyhydricalcohol containing 2 to 10 carbons and 2 to 6 hydroxyl groups and eitherethylene oxide or a heteric mixture of ethylene oxide and propyleneoxide. The resultant surfactants are heteric polymers having a molecularweight in the range of about 400 to about 1600 and containing 40% to 80%by weight of ethylene oxide, with a alpha-olefin oxide to polyhydricalcohol mole ratio in the range of about 1:1 to 1:3.

Amphoteric surfactants useful in the present invention are zwitterionshaving the capacity to act as either an acid or a base. They aregenerally non-irritating and non-staining. Non-limitative examples ofsuitable amphoteric surfactants include cocoamidopropyldimethylsultaineand cocodimethylbetaine (commercially available from Lonza Chem. Co.under the trade-names Lonzaine CS and Lonzaine 12C, respectively.

Cationic surface active agents are molecules that carry a positivecharge such as the quaternany ammonium compounds.

A fluorine providing compound may be present in the oral compositions ofthis invention. These compounds may be slightly water soluble or may befully water soluble and are characterized by their ability to releasefluroide ions or fluoride containing ions in water. Typical fluorineproviding compounds are inorganic fluoride salts such as soluble alkalimetal, alkaline earth metal, and heavy metal salts, for example, sodiumfluoride, potassium fluoride, ammonium fluoride, cuprous fluoride, zincfluoride, stannic fluoride, stannous fluoride, barium fluoride, sodiumfluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodiummonofluorophosphate, aluminium mono-and difluorophosphate andfluorinated sodium calcium pyrophosphate.

In an oral liquid composition such as a mouthwash, the fluorineproviding compound is generally present in an amount sufficient torelease up to about 0.15%, preferably about 0.001% to about 0.05%,fluoride by weight of the composition.

The compositions of this invention may be substantially solid or pastyin character such as dental cream, toothpaste, toothpowder or chewinggum. Solid or pasty oral compositions contain polishing materials.Typical polishing materials are abrasive particulate materials havingparticle sizes of up to about 20 microns. Nonlimiting illustrativeexamples include water-insoluble sodium metaphosphate, potassiummetaphosphate, tricalcium phosphate, dihydrated calcium phosphate,anhydrous dicalcium phosphate, dicalcium phosphate, calciumpyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calciumcarbonate, alumina, aluminum silicate, zirconium silicates, silica,bentonite, and mixtures thereof. Polishing materials are generallypresent in an amount from about 20% to about 99% by weight of thecomposition. Preferably, it is present in amounts from about 20% toabout 75% in toothpaste, and from about 70% to about 99% in toothpowder.

In clear gels, a polishing agent of colloidal silica and alkali metalaluminosilicate complexes are preferred since they have refractiveindices close to the refractive indices of gelling agent liquid systemscommonly used in dentifrices.

The compositions of the present invention may additionally containsweeteners, flavorants and colorants.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist:

A. Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, dextrose, sucrose, maltose, partiallyhydrolyzed starch, or corn syrup solids and sugar alcohols such assorbitol, xylitol, mannitol and mixtures thereof.

B. Water-soluble artificial sweeteners such as the soluble saccharinsalts, i.e., sodium, or calcium saccharin salts, cyclamate salts,acesulfame-K and the like, and the free acid form of saccharin.

C. Dipeptide based sweeteners such as L-phenylalanine methyl ester andmaterials described in U.S. Pat. No. 3,492,131 and the like.

In general, the amount of sweetener will vary with the desired amount ofsweetness selected for a particular composition. This amount willnormally be 0.01% to about 40% by weight. The water-soluble sweetenersdescribed in category A above, are preferably used in amounts of about5% to about 40% by weight, and most preferably from about 10% to about20% by weight of the final composition. In contrast, the artificialsweeteners described in categories B and C are used in amount of about0.005% to about 5.0% and most preferably about 0.05% to about 2.5% byweight of the final composition. These amounts are ordinarily necessaryto achieve a desired level of sweetness independent from the flavorlevel achieved from flavorants.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, citrus flavors such as orange and lemon,artificial vanilla, cinnamon, various fruit flavors and the like. Bothindividual and mixed flavors are contemplated. The flavorings aregenerally utilized in amounts that will vary depending upon theindividual flavor, and may, for example range in amounts of about 0.1%to about 6% by weight of the final composition.

The colorants useful in the present invention, include the pigmentswhich may be incorporated in amounts of up to about 2% by weight of thecomposition. Also, the colorants may include other dyes suitable forfood, drug and cosmetic applications, and known as F.D. & C. dyes andthe like. The materials acceptable for the foregoing spectrum of use arepreferably water-soluble. Illustrative examples include the indigo dye,known as F.D. & C. Blue No. 2, which is the disodium salt of5,5-indigotindisulfonic acid. Similarly, the dye known as F.D. & C.Green No. 1, comprises a triphenylmethane dye and is the monosodium saltof 4-[4-N-ethyl-p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine].A full recitation of all F.D. & C. and D. & C. colorants useful in thepresent invention and their corresponding chemical structures may befound in the Kirk-Othmer Encyclopedia of Chemical Technology, 3rdEdition, in Volume 6, at pages 561-595, which text is accordinglyincorporated herein by reference.

The present invention also involves a method for treating teeth or gumsto reduce plaque or gingivitis comprising applying to the surface of theteeth and/or gums the compositions of this invention as describedearlier. The compositions can be applied to the teeth and gums by anyconventional means such as brushing, spraying, painting or rinsing ofthe oral cavity and the like. The compositions not only retard plaqueaccumulation, but has been demonstrated to remove pre-existing plaque aswell. Additionally, the compositions show a prolonged effect on plaqueaccumulation following cessation of treatment through about one weekafter use. The compositions of this invention are also useful as atopical antiseptic or disinfectant which is applied externally to theskin.

The following examples are presented to further illustrate thisinvention. The examples are intended in an illustrative sense and not ina limitative sense. The present invention includes the embodimentsdescribed and shown and any equivalents thereof. All parts andpercentages are on a weight basis unless otherwise indicated.

EXAMPLE I

A composition within the scope of this invention was prepared by mixingthe ingredients given in Table I below. This composition was useful as amouthwash.

                  TABLE I                                                         ______________________________________                                        Ingredient         Amount (% w/v)                                             ______________________________________                                        3-(4-propylheptyl)-4-(2-hydroxy                                                                  0.01                                                       ethyl) morpholine hydrochloride                                               penicillin         10.sup.-5 molar                                            nonionic surfactant                                                                              0.7                                                        sorbitol solution (70% solids)                                                                   50.0                                                       ethanol (95% in water)                                                                           10.0                                                       coloring agent     0.0004                                                     flavoring agent    0.15                                                       deionized water    (quantity sufficient to 100%)                              ______________________________________                                    

EXAMPLE II

A composition within the scope of this invention was prepared by mixingthe ingredients given in Table II below. This composition was useful asan oral spray.

                  TABLE II                                                        ______________________________________                                        Ingredient         Amount (% w/v)                                             ______________________________________                                        3-(4-propylheptyl)-4-(2-hydroxy-                                                                 0.10                                                       ethyl) morpholine hydrochloride                                               penicillin         10.sup.-5 molar                                            nonionic surfactant                                                                              1.2                                                        citric acid; hydrous                                                                             0.07                                                       ethanol (95% in water)                                                                           12.0                                                       glycerol           20.0                                                       sweetening agent   0.01                                                       flavoring agent    0.10                                                       deionized water    (quantity sufficient to 100%)                              ______________________________________                                    

EXAMPLE III

Compositions within the scope of this invention were prepared by mixingthe ingredients given in Table III below. These compositions were usefulas a dentifrice.

                  TABLE III                                                       ______________________________________                                        Ingredient         Amount (% w/v)                                             ______________________________________                                        3-(4-propylheptyl)-4-(2-hydroxy-                                                                  0.20                                                      ethyl) morpholine hydrochloride                                               penicillin         10.sup.-5 molar                                            sodium fluoride     0.24                                                      hydrated silica    10-50                                                      xylitol            10-40                                                      xanthan gum        0.1-1.5                                                    cocobetaine        0.1-1.5                                                    flavoring agent    0.9                                                        deionized water    (quantity sufficient to 100%)                              ______________________________________                                    

We claim:
 1. A composition having synergistic anti-plaque oranti-gingivitis activity comprising in combination a synergisticpharmaceutically effective amount of a) a morpholinoamino alcohol orpharmaceutically - acceptable salt thereof, wherein said morpholinoaminoalcohol has the chemical formula ##STR8## wherein R₁ is a straight orbranched alkyl group containing 8 to 16 carbon atoms at the 2- or3-position of the morpholino ring, and R₂ is a straight or branchedalkyl group containing 2 to 10 carbon atoms terminating with a hydroxygroup and (b) an antibiotic, wherein the amount of said morpholinoaminoalcohol or salt thereof ranges from about 0.1% to about 5% by weight,and the amount of said antibiotic ranges from about 10⁻³ molar to about10⁻¹⁰ molar based on total weight of said composition.
 2. Thecomposition of claim 1 wherein said antibiotic is selected from thegroup consisting of aminoglycosides, amphenicols, ansamycins,carbapenems, cephalosporins, cephamycins, monobactams, oxacephems,penicillins, lincosamides, macrolides, polypeptides and tetracyclines.3. The composition of claim 2 wherein said antibiotic is selected fromthe group consisting of B-lactams, monobactams, tetracyclines andpolymyxins.
 4. The composition of claim 1 wherein the sum of the carbonatoms in said groups R₁ and R₂ is 10 to
 20. 5. The composition of claim1 wherein said morpholinoamino alcohol is3-(4-propylheptyl)-4-(2-hydroxyethyl) morpholine.
 6. The composition ofclaim 1 wherein said pharmaceutically-acceptable salts are the salts ofacids selected from the group consisting of acetic acid, phosphoricacid, boric acid, hydrochloric acid, maleic acid, benzoic acid, citricacid, malic acid, oxalic acid, tartaric acid, succinic acid, glutaricacid, gentisic acid, valeric acid, gallic acid, beta- resorcylic acid,acetyl salicylic acid, salicylic acid, perchloric acid, barbituric acid,sulfanilic acid, phytic acid p-nitro benzoic acid, stearic acid,palmitic acid, oleic acid, myristic acid and lauric acid.
 7. Thecomposition of claim 1 wherein said composition is a tooth paste.
 8. Thecomposition of claim 1 wherein said composition is a liquid mouthwash.9. The composition of claim 1 wherein said composition is a chewing gum.10. The composition of claim 8 wherein said mouthwash comprises up toabout 30% by weight alcohol.